Peptides are a revolution and you don't need to know how they work to know that they work (for various people for various conditions). There is a tension between empiricism and fundamentalism with much of medical science focusing on fundamentalism. Now with the ability to collect and search large amounts of empirical data and communicate it peer-to-peer people are picking up on a lot of things that work without knowing why they work. I think people are just going to circumvent the fundamentalist and chase after whatever works.
I owe my health to early adoption of experimental peptides, I have life long ME/CFS and there is no known treatment for this nor is there any on the horizon. At least they finally have a diagnostic test and know it's not psychosomatic but I could have told them that from day 1. Most doctors are not researchers and have little understanding on statistics instead preferring to rely on discrete classifications and simple decision tress. As someone with hEDS from TNXB I am a walking bag of symptoms and yet not a single doctor could figure it out. I had to research it myself which involved post-doc level textbooks and research journals. I came across the work done by Prof. Khavinson (USSR) and it did appear to me that peptides were incredibly under-explored. Given the poor quality of life with ME/CFS I was willing to take serious risks so previous trials were helpful to give an idea on dosing and lethality, I went through most of the research peptides one by one. I actually waited on semaglutide a bit because I suspected there was a small minority who would have hyper sensitivity and I both expected that to appear in the data, which it did, and I expected to have hypersensitivity, which I did. Others who were less careful ended up with pretty bad gastroenteritis. Semaglutide has been the most effective and with it and a few others I am largely able to lead a normal life. I was getting gray market from the US but now I get it direct from China.
> There is a tension between empiricism and fundamentalism with much of medical science focusing on fundamentalism.
This is a deeply unfair statement, and also a false dichotomy. Medical science is of course empiric. What you call "fundamentalism" is that compounds need to undergo a rigorous regiment of empiric testing before they are given to potentially millions of people. And no, it's not just because of Thalidomide. Many, many compounds fail clinical trials because of severe side effects, like liver toxicity, severe immune reactions or heart problems. Then there's of course increased risk of cancer, which can take many years to manifest itself empirically. You argue that you prefer living with these uncertainties rather than ME/CFS, and that's of course entirely understandable, but disparaging the field of medical science as focused on "fundamentalism" because we do not give large patient cohorts untested compounds is polemic. I understand where you are coming from, and I'm sorry that you suffer from this terrible condition, but likewise, you should try to understand the other side.
Doctors have been maligning ME/CFS as psychosamatic for decades and generally still do despite a large amount of modern evidence to the contrary. If you have it it’s clearly not, you can get good and bad days that are clearly not dependent on psychological state. In addition I have it due to hEDS which is a condition that is almost never diagnosed due to aforementioned blind spots. Most doctors still think the prevalence rate is 1/50K despite continued research raising that number to 1/15K and 1/500. It takes a long time for this information to percolate through the system.
Doctors, like many professions, have institutional blind spots, I studied these in my search because I was looking for something that had not been found. Most doctors have to consider all people and all conditions, I only have to be concerned with one.
Notably they only recently adopted Bayesian statistics for medical trials despite that math being around for hundreds of years.
I completely understand your frustration with the lack of knowledge and research in ME/CFS. It's a scandal, given the prevalence and seriousness of the condition. Unfortunately, after Covid, ME/CFS was even more politicized as part of the long-Covid discussions and got caught up in the culture wars. I have several friends with ME/CFS and they basically say the same things you do - ignorant doctors, high cost due to medication usually being off-label and not covered by insurance, and even friends don't take the condition seriously.
ME/CFS research is severely underfunded. The reasons for this are not simple, it's partly due to the complexity of the disease which, as cynical as it is, does not make it an attractive research topic for ambitious scientists. Same goes for "Big Pharma". Clinical trials for ME/CFS are extremely complicated, and hence expensive, due to the myriad of symptoms in how the condition can appear. It makes research in this area very difficult and expensive. There's very little funding for ME/CFS research, and that needs to change. Unfortunately, especially in the US, this is not going to happen for Kennedy reasons.
The Bayesian statistics thing is a bit of red herring, though. While your are correct that the math is old, the needed compute resources for doing Bayesian modeling on large trials was simply not there until recently. But it is also correct that it also took a long time until there were official rules regarding this from FDA and EMA. These regulatory things move very, very slowly.
Unless you’ve had ME/CFS you cannot understand how bad it is, I’ve had it and I still have a hard time comprehending how bad it was, I am occasionally reminded and it’s easy to forget. While it won’t kill you it’ll destroy your life until you’re ready to kill yourself.
The UK led the world with explicit psychologizing of it in large part to prevent insurance companies being liable for such an expensive and debilitating condition. A legacy that continues to this day, the main people responsible are still very influential. Fauci was instrumental in diverting research away from the autoimmune aspect and preventing a lot of important research. The $1B set aside for LongCovid appears to largely have been wasted. The official classification for hEDS was explicitly changed to reduce the number found so that it could remain a rare disease and continue to have access to specific funding for rare diseases (goal seeking). I could go on and on. It is a highly dysfunctional industry with many perverse incentives pulling it in all sorts of directions. There was the healthy at any size movement despite obesity being a massive cause for mortality, perhaps the only stronger signal would be smoking and consider how long it took them to figure out smoking.
There have been insanely impressive improvements to medical science but this seems to be largely due to tooling and access to information rather than the lumbering bureaucracy which appears to do very little of benefit.
I don't really understand where you are going with the fundamentalist vs. empiricist holy war narrative. Medical science is very empiricist, but it is conservative.
Yes they will miss rare cases or where symptoms aren't quantifiable or where no understood biological mechanism exists. Yes you can take on research and treatment yourself with the risk associated. No a bunch of anecdotal evidence on experimental treatments do not substitute for structured research. No you won't come back here in 3 years if you develop serious side effects that would have been identified in clinical trials and tell everyone you were wrong.
’fundamentalist’ has religious connotations which I did not intend, I meant deduction from first principles not foundational orthodoxy. My expression was there was tension not completely discrete factions, there is clearly some empiricism used in medicine. One of the difficulties in getting published is defending a position and it’s easier to do this with a mechanism of action which I think slows things down too much. The pace of progress on my conditions might as well be none at all. Still no cure for a condition that’s been known about since Hippocrates.
So I’ve been doing this for over 4 years now, and commenting on this with this account for a bit less than that, so far no serious unwanted side effects other than the usual ones for semaglutide which went away. Of course that has a survivorship bias but in the forums people do often tell others what they’re about to try and we would notice if they stopped showing up.
> My expression was there was tension not completely discrete factions, there is clearly some empiricism used in medicine. One of the difficulties in getting published is defending a position and it’s easier to do this with a mechanism of action which I think slows things down too much.
There is always tension between objectives in real-world systems. There are essentially two frontiers in our healthcare system--a core of educated professionals that are conservative and move slowly with ample evidence behind decisions, and a wide range of laymen who are comfortable with personal risk (e.g. bodybuilding community). I have respect for both, and they work together. The core will always have too many false negatives and the horizon group will have too many false positives. Saying the balance right now slows things down too much needs more support as an argument, there will always be things on the roadmap for medicine and there will always be edge cases that can't get addressed perfectly
From what I've seen medical researchers are champing at the bit for new areas of treatment that they think are promising and they just need the smallest amount of convincing evidence to research. If they don't have it for something you think is valuable, collect the information in a systematic way and find someone to send it to.
>compounds need to undergo a rigorous regiment of empiric testing before they are given to potentially millions of people
Particularly when the mechanism behind most of these peptides comes down to "promotes more rapid cell growth". The intent may be to repair the skin, muscles, or ligaments, but biology is rarely that specific.
I think the grandparent meant "fundamentalism" as "mechanistic", and lots of things we can know (as you say using the scientific method) to be useful long before we have a good mechanistic explanation of how they work.
Some examples: aspirin (willow bark used for thousands of years, drug synthesized in 1897 and mechanism explained almost 100y later), or general anesthesia used again since mid 1800s and the mechanism is quite still debated.
This is not to downplay all the long term, or developmental, risks that using something novel can result in. But we can empirically know something about the effects without having good mechanistic models.
But it is usually not necessary for approval of a compound to be able to describe how it works on a molecular or cellular level. What you need to show are three things: efficacy, safety and quality, so basically: the compound has the intended clinical benefit, has an acceptable safety profile and can be produced with a consistent manufacturing quality. Most compounds fail because of lack of efficacy (roughly half), and roughly a third because of lack of acceptable safety.
The vast majority of drug candidates don’t make it to the trial stage. Much of the research has to be defensible prior to the trial and what makes them defensible is having a mechanism for action. Of course once a drug is being used off label there starts to be some empirical data which can be used for trials, and it seems that we’ll get lucky with GLP1-As.
You are entirely correct. New compounds for trials do not come out of thin air, you usually derive them from compounds you already know how and why they work. For instance, we know very well how Semaglutide works, same goes for many other peptides that are currently being studied. However, you are correct that we do not understand why they would help for ME/CFS, simply because we do not understand ME/CFS in the first place. As I've written above, it's a severely neglected disease.
Anyway, I don't think we really disagree, I rather misunderstood your original post. It's good to hear that these new peptides are helping with your condition, and I wish you all the best!
Thanks for the feedback, I’m noticing that ‘fundamentalism’ didn’t translate properly and I should have referred to first principles and mechanisms of action. I need better words for these and I will try to find them.
As a fun aside, consider the effect of the birthday paradox on empiricism, as the pool of candidates grows larger the probability of a match increases substantially as potential matching candidates increases quadratically.
Non blinded self experimentation is not a useful branch of empiricism.
I had an ME/CFS patient that had tried 100s of things and documented the effects thoroughly. She had a quite impressive list. Roughly 30% had had an effect to begin with, but the trend she observed was that it lasted for around a month at most. Placebo was her overall conclusion, but she occasionally got relief anyways so we both agreed that there was no harm in continuing. I'm sure several "peptides" is on her list by now.
There is nothing new under the sun, and fad cures for diffuse conditions have come and gone many times before. This is especially the case for conditions involving pain or tiredness, which are extremely sensitive to both placebo and nocebo.
What would be revolutionary would be 2-3 double blinded RCTs showing a lasting effect. Which would be great if someone did! But you have to actually bother to do it. And personally I would put money on the outcome being "no effect".
What do you think about the mis-alignment between goals here?
For medical research, the goal is to find general practices that will broadly help, and identify risks with the intervention. Even then, with many interventions, it's understood that they will effect people differently.
For individuals, they don't care about variation in communities, or standard medical practices, they are looking for relief for their specific condition.
Of course, declaring that just because something worked for one person, it should work for others, is wrong in both camps.
I feel like a big part of the disconnect here, and a big reason why people are talking past each other, is that they actually have different goals, and aren't really aware of that difference.
Well, to be honest I think the primary disconnect is in epistemological understanding. The OP did not declare peptides to be a personal revolution, he/she seemingly generalised their own experience to be widely applicable.
Basic human thought patterns usually lead people to think that anecdotes about their personal experience is valuable for understanding the world, but this is wrong. The scientific revolution basically illustrated the flaw in this premise outside of hypothesis generation. It takes specific education to make human beings truly believe that their anecdotal experiences are mostly irrelevant beyond understanding their immediate circumstances. The proportion of humanity that truly think this way is relatively small.
Understanding the world through anecdotes still works okay-ish for a lot of areas, but ascertaining relatively subjective effects of experimental pharmaceuticals is not one of them. But to many people it's non obvious that this is the case. And as a general method of thinking about this issue, it is just the wrong way to go about things.
And that's the disconnect, in my opinion. The OP drew a conclusion from a thought pattern that comes easily to human beings, but that is just wrong in this situation. Of course, perhaps this is reinforced by underlying motivations, but that's not what makes people talk past each other. These kinds of discussion are usually driven by so called "deep disagreements" in epistemological understanding, in my experience.
I'm pretty sure there is no diagnostic test for ME/CFS. What are you referring to?
Also I don't understand how semaglutide did help you while you're at the same time part of a minority risk group with a hypersensitivity to it. Isn't that a contradiction?
Yes, sensitivity at over 10x normal, so I just took 10x less. I’m taking a more normal dose now after 4 years and I believe I have become desensitized as my body normalized. Other seemingly unrelated aspects also normalized such as thyroid, testosterone, and neutrophils also improved. I was taking medication for these and have been able to stop taking them. I am assuming a lack of GLP1-As to begin with caused the receptors become more sensitive to it. When I started there was no anecdotal information available just theory, in the 4 years since many people have now had very similar experiences including hypersensitivity. (https://www.healthrising.org/blog/2025/11/03/glp-1-agonist-m...)
There are now a number of very definitive tests, most related to immune system profiling. Prof. Ron Davis has some good research and has shown that plasma from someone with ME/CFS when combined with normal red blood cells will greatly diminish the ability for red blood cells to handle stress (pumping out salt).
I think I would need to see testing on a control group of housebound patients with other conditions to believe this. It's easy for ME testing to pick up markers for being housebound and limited exercise for an extended period of time.
You sound exactly like the tens of doctors that misdiagnosed my aunt (who passed away through euthanasia after her symptoms got too bad to live with late last year).
I understand that the symptoms of ME/CFS might be similar to being obese/depressed or housebound, but the problem is that doctors often jump to that conclusion too quickly and don’t take efforts to diagnose ME/CFS leading to situations like my aunt’s. She was also obese and depressed and has been struggling with those symptoms for about 30 years and has constantly been misdiagnosed the entire time because doctors didn’t figure out that those were symptoms of ME/CFS and not two unrelated conditions coming from two different diagnoses.
Thanks to long-covid putting the symptoms of ME/CFS on the forefront lately, there’s finally been some much needed research into the disease and people like my aunt finally get the diagnosis they should have been getting many years ago.
Sorry to hear about your aunt. My condolences. I think your misinterpreted my intent, I would dearly love a good diagnostic test for ME/CFS and agree research has been hugely underfunded.
I have followed closely the research for many years and there has been false promise of good diagnostic tests previously. What I'm arguing for is that we need a test that is specific for ME/CFS. E.g. it will test positive for a patient with ME/CFS regardless of they are obese or not, but more importantly it will not test positive for everyone who is obese. This is known as the sensitivity and specificity of the test.
What I've seen in the past is some previous ME/CFS tests show positive for groups with related symptoms but who don't have ME/CFS. This then becomes a worthless diagnostic tool. For example this would not have helped your aunt.
Well, reading the study, I'm not sure more patients could rescue it from methodological bias. They assumed the premise basically -- we should find a biomarker, which is kind of what this thread is discussing. Then they went trawling for biomarker in a sea of millions of biomarkers. They did this by training an model that produced the desired result, using a grid search for hyper parameters that even further expanded the available degrees of freedom here beyond what they had from the biology. No pre-registration; There are millions of places where the researchers could have made a different decision -- would they still have gotten a publishable result? Oh plus the authors mostly work for the company whose data they use, which is hoping to sell a diagnostic test.
I'm giving you a thorough response because I'm detecting a cavalier anti scientism which I think is sadly becoming more common. This stuff is hard; are you sure you understand it enough to have an informed opinion?
Im sorry for your quality of life problems but calling doctors bad at statistics and then giving anecdotal evidence as proof has to start ringing some logical bells right? You dont even have to take our word. Use an LLM as judge. Paste your comment into chatgpt and see what it says.
I didn't read their whole comment, but I worked in the Internal Research department of a medical school. I did their statistical studies and built software for analysis pipelines.
Doctors, at least 15 years ago, were definitely bad at statistics.
They were not required to take a statistics course at all. Most programs would require Algebra and Calculus as part of their science reqs.
Some would maybe take one basic research course, and they would then become obsessed with p values of 0.05.
They did not have a basic understanding of how to interpret research unless they were an auto didactic and went out of their way to improve. It's something my director (a doctor and software engineer), and the Dean complained about relentlessly.
I’ve not only visited many doctors personally I was also part of a team working on a medical diagnostic instrument, the result of the instrument was a probability distribution function and it was impossible to explain this to the doctors who really would only accept a small number discrete classifications, which in effect throws out about half of the data we had worked so hard to collect.
You reminded me about another idiosyncrasy:
Doctors are addicted to double blind randomized control trials.
Which yes, those are powerful. But good evidence can come from many other study designs. Especially when mechanisms and first principles are being studied.
I guess it depends on how you frame it. "I've just posted this comment, what do you think" vs "Someone online has just posted this comment, what do you think".
But it does require to know the bias that LLMs have ahead of testing this.
I agree with this, but we don't have a good understanding of the mechanisms of how most drugs work, and what else they do. That's why, generally speaking, we require actual observational safety data, and not just a thorough description of the mechanism(s) of a drug. And sometimes we find out years or even decades later we were badly wrong. "Safe" is a very qualified term when it comes to drugs. What actually distinguishes $randompeptide from $approveddrug is the safety data - there are papers all about the proposed mechanisms for most of them.
If a lot of people take the mediation and die is that evidence that the medication is unsafe? If they live is that evidence that the medication is safe? Either both are true or neither is true. The relative weight of evidence is dependent on priors but it is still evidence.
Your comment reads like someone with no experience in medical trials - neither pharmaceutical nor medical devices. Death is not the only negative outcome. Nor is a procedure that is commonly followed by death necessarily a bad procedure - many cancer treatments for example fall into this category.
You’re not understanding the point of the hypothetical, it was to illustrate a scenario in that most people would consider evidential and point out that by definition the opposite outcome must also be evidential even if that outcome was far more likely. It’s to highlight an unintuitive aspect of probability formalized as the bayes ratio. The strength of the evidence is dependent on the priors but it exists. Anecdotal evidence is not zero evidence it is weak evidence and with care a lot of anecdotal evidence can be combined to create stronger forms of evidence. Rounding it down to zero or up to one are both incorrect.
And yet neither of the sides are strong enough to term as evidence. I have no problem with self-experimentation. But citing a few anecdotes as evidence is a dangerous area that I discourage. Somedau we will understand why some people respond so favourably to the wolverine stack and others don't. And somebody will someday correlate what those hurt by BPC-157 all have in common. But until then, these peptides cannot be recommended to others in good conscious.
That is so dangerous, buying grey market replicas of pharmaceuticals.
Unless you have a research lab built out in your house, you have zero way of knowing what it is that you're actually getting. Whether the dosing matches the claimed dose. Whether there are bacterial growth, or other manufacturing chemical left in by bottom-of-the-barrel chinese manufacturer.
I understand your risk profile may be different than others, but when you can get the real thing officially, I'm not sure why anyone would risk this.
Clinical trials are not looking for fundamental mechanisms, they are there to ensure an effect is strong enough to say a product should be sold for that purpose. Otherwise you end up with snake oil salesmen. Because how can you be sure you are even injecting the thing the sellers claim it is?
I would encourage everyone interested in peptides to read about the state of medical science before the establishment of the Pure Food and Drug Act of 1906.
I have tried everything on just about every list of possible treatments, having been in the fortunate position to have made enough money that I can try things full time and being able to bypass doctors for access to medicine and being able to do my own research.
I don’t know the mechanism, I think ME/CFS is an autoimmune condition and semiglutide appears to help with autoimmune conditions in general. That was my reason for trying it. The improvements snuck up on me after many months as I noticed I was having fewer and fewer bad days.
If you felt improvements with semiglutide only after many months, how long did the other trials last? It sounds like you went through hundreds of trials. Did they all went on for many months? When did you determine that a drug wasn't effective and abort the trial? How come you didn't abort the semiglutide trial earlier?
Because I started at such low dose 0.025mg and ramped slowly I didn’t expect to see much of an effect until I got to more normal doses so I was unusually patient with it. Additionally extended water fasting (>5 days) was the only thing helping my headaches so I was focusing on ways to emulate this effect without an unmaintainable amount of fasting. I also had uncontrollable weight gain so I figured that was either related, or if not it would still help to lose weight anyway.
Most of the stuff I’ve tried that worked usually has an immediate or overnight effect. Notably Low Dose Naltrexone was overnight, Low Dose Abilify was near immediate. I believe this is due to their immunomodulator properties. So I studied psychopharmacology and focused in on finding weaker ligands than typical as a way to try and safely modulate my immune system. I landed on Modafinil in the morning and Amitryptiline at night, both off label treatments for the probably related dysautonomia.
The N of 1 with many overlapping signals and medications was of course very noisy but I treated it like a ML optimization problem. I could tell it was likely beneficial within the first week even with the small dose. I probably could have statistically determined it was working within a few months but I was distracted by work so it took a little longer to be sure.
Placebos would work with anything with a plausible story, since I’ve tried many hundreds of things and only a handful worked I’m highly confident that it’s not a placebo. People with ME/CFS are used to trying things and have them not work so the placebo effect where it exists has usually worn off.
I owe my health to early adoption of experimental peptides, I have life long ME/CFS and there is no known treatment for this nor is there any on the horizon. At least they finally have a diagnostic test and know it's not psychosomatic but I could have told them that from day 1. Most doctors are not researchers and have little understanding on statistics instead preferring to rely on discrete classifications and simple decision tress. As someone with hEDS from TNXB I am a walking bag of symptoms and yet not a single doctor could figure it out. I had to research it myself which involved post-doc level textbooks and research journals. I came across the work done by Prof. Khavinson (USSR) and it did appear to me that peptides were incredibly under-explored. Given the poor quality of life with ME/CFS I was willing to take serious risks so previous trials were helpful to give an idea on dosing and lethality, I went through most of the research peptides one by one. I actually waited on semaglutide a bit because I suspected there was a small minority who would have hyper sensitivity and I both expected that to appear in the data, which it did, and I expected to have hypersensitivity, which I did. Others who were less careful ended up with pretty bad gastroenteritis. Semaglutide has been the most effective and with it and a few others I am largely able to lead a normal life. I was getting gray market from the US but now I get it direct from China.